Centre for Medical Research and Translation, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China.
Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Cell Death Dis. 2024 Sep 3;15(9):642. doi: 10.1038/s41419-024-07026-5.
Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.
配对免疫球蛋白样受体 2 型β（PILRB）主要在调节先天免疫中发挥关键作用，但 PILRB 是否参与癌症尚不清楚。在这里，我们报告 PILRB 通过结合和稳定 IRS4 来增强 PI3K/AKT 通路，从而驱动胃肿瘤发生，这可能会过度激活 PI3K/AKT 通路。首先，PILRB 的水平在人胃癌（GC）标本中上调，并与 GC 患者的预后不良相关。此外，我们的数据表明，PILRB 在体外和体内促进 GC 细胞的增殖、集落形成、细胞迁移和侵袭。在机制上，PILRB 将去泛素化酶 OTUB1 招募到 IRS4 上，并减轻 IRS4 的 K48 连接泛素化，保护 IRS4 蛋白免受蛋白酶体介导的降解，并随后激活 PI3K/AKT 通路。重要的是，GC 标本中 PILRB 的水平与 IRS4 呈正相关。同时，我们还发现 PILRB 通过改变 ABCA1 和 SCARB1 的表达水平来重新编程胆固醇代谢，PILRB 表达使 GC 细胞对他汀类药物治疗产生抗性。总之，我们的研究结果表明，PILRB 在胃肿瘤发生中的致癌作用为 GC 中 PI3K/AKT 信号的调节提供了新的见解，并确立 PILRB 为 GC 中辛伐他汀治疗耐药性的标志物。
